While the anticonvulsant and antinociceptive effects of carbamazepine appear acutely, more chronic administration is required for maximum onset of antimanic and antidepressant efficacy. These data suggest that different mechanisms of action may be associated with anticonvulsant, antinociceptive, and psychotropic effects of this drug. Carbamazepine exerts important anticonvulsant actions via peripheral-type benzodiazepine receptors. In addition, unblocked alpha2 receptors appear to be required. Antinociceptive but not anticonvulsant effects of carbamazepine have been thought to involve GABA-B mechanisms. Therefore, we undertook a clinical trial of L-baclofen in affectively ill patients and found that it was not only ineffective but may have exacerbated depression. These data suggest the potential utility of exploring GABA-B antagonist strategies in bipolar illness. Dr. S. Weiss has developed an animal model that requires chronic administration in order to demonstrate anticonvulsant efficacy. Thus, the ability of chronic, but not acute or repeated intermittent, carbamazepine to block the development of cocaine- and lidocaine-induced kindling may provide a series of important leads to possible mechanisms of the psychotropic effects of carbamazepine (which also require chronic administration). Based on these studies, we have found that alpha2 noradrenergic, cholinergic, serotonergic, and somatostatinergic mechanisms are not required and a role for corticotropin releasing hormone has not been definitively demonstrated. A variety of candidate systems remain to be explored including carbamazepine's ability to upregulate adenosine receptors, as well as its effects on other ion channels, neurotransmitter, neuropeptide, and second messenger systems. It is hoped that once the mechanism of action of carbamazepine is elucidated, it might lead to the development of newer, more selective treatment agents for the refractory affective illnesses. Based on a variety of clinical and preclinical findings, we have initiated a study of intrathecal TRH in the treatment of refractory depressed patients.